Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

Abstract

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23-30 kg) were randomized to sham (N ϭ 8) or hepatic devascularization ALF (N ϭ 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased Ͼ85% of the basal level at t ϭ 6 h (P Ͻ 0.001), whereas citrulline and ornithine progressively increased in ALF (P Ͻ 0.001 and P Ͻ 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis (P Ͻ 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF (P Ͻ 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.arginine; asymmetric dimethylarginine; arginase ACUTE LIVER FAILURE (ALF) is characterized by sudden and severe liver dysfunction with rapid progression to coagulopathy, encephalopathy, and multiorgan failure. Without liver transplantation, mortality from ALF is about 50% (4). A hallmark of ALF is the presentation of systemic hypotension and a hyperdynamic circulation (39). This is associated with increased guanylate cyclase (GC) activation by nitric oxide (NO) (33), which converts guanidine triphosphate to cyclic guanidine monophosphate and is thought to cause the vasodilatation seen in ALF (34). Previously, we have reported the characteristics of the same devascularized porcine liver model of ALF, which was shown to have a hyperdynamic circulation as evidenced by a high cardiac output and low mean arterial pressure and systemic vascular resistance (50). However, in this hyperacute model of ALF, no significant changes in the metabolites of NO were observed. Indeed, the kinetics of NO in this model and whether it is involved in the initiation of the vasodilation of ALF remain unknown.L-Arginine has several important biological functions (2, 3, 5), one of which is to be the nitrogen-donating substrate for endothelial NO synthase (eNOS) to produce NO and citrulline in stoichiometric quantities (...

Effect of Nitric Oxide Pathway Regulation on Water/Sodium Balance and Renal Function in a Rodent Model of Acute Liver and Renal Failure

“…Total removal of vascular endothelium (a source of NO biosynthesis) repairs impaired vascular reactivity to the above-mentioned vasoconstrictors [ 39 ]. In a recent study, Sharma et al [ 40 ] showed that the total NO production in the first hours of acute liver ischaemia in large experimental animals is similar to that in the sham group. However, this finding was based on models of acute liver failure, not typical HRS, observed only during the first 6 h after induction of liver injury; moreover, the animal species used in that study was different from those used in our study [ 40 ].…”

Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation

“…The issue of arginine metabolism and its influence on the hepatobiliary system is widely discussed nowadays [10][11][12]. In a human body L-arginine may be synthesized in liver provided by the balanced ration with both quantitative and qualitative composition of a dietary protein being of fundamental importance [13,14].…”

Role of DDAH/ADMA pathway in TGF-β1-mediated activation of hepatic stellate cells

“…The activation of HSCs is well recognized as a central event in hepatic fibrosis, which involves a range of signaling pathways. A number of studies have shown that ADMA, an endogenous molecule (23), is associated with the severity and progression of liver damage (15,(24)(25)(26)(27). In a study by Li et al (28), it was important to note that excessive ADMA significantly induced mRNA expression of α-SMA, increased α-SMA-positive cells ratio, and synthesis of type I collagen in dose-and time-dependent manners in HSCs through, at least in part, the ROS-NF-κB molecular pathway, which suggests that ADMA is involved in the activation of HSCs as a potentially novel mediator of transformation of HSCs (28).…”